Cryptococcal Disease - 2/22/2013

At CRS today, we proceeded through a case of a
young man with advanced AIDS who presented with a couple of weeks of
respiratory symptoms, fevers, and new papular skin lesions. Workup ultimately
revealed disseminated cryptococcemia – interesting case. So, I’d thought I’d
take this opportunity to talk about this fantastically fun fungus:

·What’s
the deal with Cryptococcus – where does it live? Why is it pathogenic? Who does
it effect?

·How can
it present clinically, and how is it diagnosed?

·What are
the treatment options? What’s the prognosis?

What’s the
deal with Cryptococcus – where does it live? Why is it pathogenic? Who does it
effect?

·First, a nice history lesson. The first case of
Cryptococcus EVER was in 1895, in a poor young woman with a leg ulcer over her
right tibia. On autopsy, yeast forms were detected on the ulcer, and those same
yeasts were detected in several other organs in her body. A couple of decades
later, the first case of Cryptococcus meningitis was documented. It wasn’t until
around the 1950s that the two predominantly pathogenic Cryptococcal species got
their names – Cryptococus neoformans
and Cryptococcus gattii.

·C.
neoformans has been isolated from soil samples worldwide, with a particular
predilection towards areas frequented by birds (especially pigeons (DAMN
pigeons) and chickens) and their excrement…it also seems to have developed a
niche in rotting wood and vegetation. It’s thought that birds harbor
Cryptococcus in their GI tract and act as a vector from vegetation to the
soil/dust that humans are exposed to. Cryptococcus
gattii is interesting in that it has a particular geographic distribution
(tropic and subtropic areas), has never been cultured from bird poop, and has
developed a niche within Eucalyptus trees
(exported from Australia to various parts of the world)…

·There are three main reasons why Cryptococcus is
pathogenic:

oFirstly, it can grow well at mammalian body
temperatures, obviously a prerequisite for all pathogenic fungi.

oSecondly, its polysaccharide capsule is central to
its pathogenesis. Mutant variants that are hypocapsular or acapsular are
rendered markedly less virulent or non-virulent. The capsule serves a number of
beneficial functions for the pathogen, but most importantly impairs antibody
binding and phagocytosis.

oThirdly, most pathogenic strains of
Cryptococcosis have the ability to synthesis melanin, which coats its cell wall
and serves as an antioxidant that protects against the oxidative guns of immune
cells. Similar to the scenario with the capsule, mutant strains without the
enzyme needed to make melanin are avirulent in animal models.

·As I’m sure we all know, C. neoformans is one of the characteristic opportunistic infections
seen in immunocompromised patients. Though most commonly seen in AIDS patients
with CD4 counts below 100, it is also seen after prolonged treatment with
glucocorticoids, advanced hematologic malignancies, organ transplantation,
cirrhosis and DM. Importantly, up to 10-15% of cryptococcal infections occur in
normal hosts without any identifiable risk factor.

·Prior to the AIDS era, cryptococcal disease was
rare – 0.8 cases/million persons/year. In 1992, the peak of the AIDS epidemic,
it became much more common – 5 cases per 100,000 persons/year. With ARVs, the
incidence has stabilized and decreased to around 1 case per 100,000
persons/year.

oImportantly, cryptococcal disease is extremely
prevalent in sub-Saharan Africa and a big killer. In this region, some reports
have cited that 15 to 45% of patients with advanced AIDS succumb to cryptococcal
infection, with incidence rates in ARV-naïve cohorts as high as 14 cases/1000
persons/year. Though the data is not as precise as it is here, still pretty
unbelievable.

How can it present clinically, and how is it diagnosed?

·The large majority of cases of Cryptococcus
manifest in either the CNS (around 50%) or the lungs (around 30%), which is
where the fungus initially sets up shop before it proliferates and
disseminates. I’m going to focus on these two sites, BUT other common sites of
infection:

oSkin - papular lesions with ulcerated centers,
usually a sentinel finding for disseminated cryptococcemia, i.e., fungus in the
blood

oProstate - usually asymptomatic, but remarkably
difficult to eradicate, serving as a sanctuary from antifungal therapy for these
critters

oEye - can be catastrophic and lead to blindess,
either due to endopthalmitis (severe inflammation of the vitreous cavity) or
compression of the ophthalmic artery due to increased intracranial pressure.

oOther – bone lesions, peritoneum (mainly in
patients undergoing peritoneal dialysis or patients with advanced chronic liver
disese)…basically ANY site in the body has some case report associated with it…

·CNS cryptococcosis is the most prevalent
manifestation of infection, especially in HIV patients, and is the main
contributor to Cryptococcus related mortality. Most patients present over 2-4
weeks with fever, malaise and headaches…nuchal rigidity, photophobia and
vomiting actually occur in a minority (20-30%). It can also present acutely
over days, but such a presentation is less common.

oCSF cryptococcal antigen is an extremely
accurate test, with sensitivity ranging from 95-100%, and specificity around
94-98%.

·Pulmonary disease has a variable presentation,
from asymptomatic to ARDS – the presence and severity of symptoms correlates
well with the degree of immunosuppression. Radiologic findings are also
variable. In normal hosts, the most common finding are solitary or multiple
nodules, but all types of imaging findngs are possible…importantly, in
immunocompromised patients, alveolar/interstitial infiltrates are particularly
common and often mimic PCP. Occasionally, the radiograph may show nothing – in
one series of 20 AIDS patients with symptomatic cryptococcal PNA, 4 had normal
chest films.

oDiagnosis of Cryptococcus infection outside the
CNS depends on imaging findings, positive serum cryptococcal antigen titers,
and positive respiratory cultures. Even if no CNS symptoms are present, for
patients who are at high risk for disseminated disease CSF exam should be part
of the workup, as it alters management…

What are some general treatment principles? What’s the
prognosis?

·For patients with good prognostic factors (lack
of diffuse infiltrates, non-CNS/disseminated infection, titers < 1:512),
oral fluconazole is pretty efficacious. Regardless of immune status, patients
with limited cryptococcal pulmonary disease are treated with fluconazole, 400
mg/day for 6-12 months. In studies of immunocompromised patients not due to
HIV, outcomes were similar when compared to amphotericin B, and overall 1 year
survival was 95%.

oHIV patients should generally be treated with
suppressive therapy after completing the initial course, at 200mg/day. If the
CD4 gets above 100 and the cryptcoccal titer is low and not increasing,
stopping suppressive therapy can be considered.

·CNS or dissemintated disease is a different
ballgame. The importance of “fungicidal” therapy takes precedence, and
randomized trials have shown that initial induction therapy with fluconazole
(“fungistatic”) leads to higher mortality and slower CSF sterilization.
Furthermore, combination fungicidal therapy in randomized trials leads to
faster sterilization rates and lower relapse rates, without a significant
increase in toxicity. The specific guidelines differ based on etiology/presence
of immunocompromise, renal function and other parameters…but here are some
generalized recommendations:

oInduction therapy should be given with
amphotericin B (0.7-1 mg/kg/day) plus flucocystine (100 mg/kg/day) for a 2-4
week duration. During this timeframe, if CNS infection has been documented, it
is imperative to reduce CSF pressure (by at least 50% or to a normal pressure -
≤20mm H2O) and document sterilization of the CSF before moving on to
consolidation and maintenance therapy…

oAmphoterrible has a host of adverse effects –
infusion reactions can be minimized by concurrent Tylenol/antihistamines, and
renal complications can be minimized with pre/post saline administration.

oAfter induction therapy, consolidation therapy
is given with fluconazole at 400 mg/day for around 8 weeks, followed by
maintenance therapy at 200 mg/day for 6-12 months.

·An important caveat to cryptococcal treatment is
IRIS. Studies have described an incidence as high as 20% in AIDS patients, and
5-10% in HIV negative patients. Generally, this occurs during the induction
phase of treatment, and manifests clinically as symptoms related to increasing
intracranial pressure. Diagnosis of HIV-related IRIS is very much dependent on the time
course of ARV initiation and symptom onset, documenting response to ARV therapy (drop in viral load more important than CD4 increase), and
negative CSF cultures…I believe I wrote a daily on IRIS…take a look!

·As mentioned, the bad-end of the prognosis
spectrum is mainly attributable to CNS disease. Unsurprisingly, patients with concurrent
malignancy have the worst survival (median of 2 months), though HIV-related
disease isn’t too great either – 10-week mortality of 10-25%. Poor prognostic
factors include a high antigen titer (>1:32), positive India ink exam, and
low inflammatory count (<20 cells) at initial LP – overall representative of
a common theme – if you can’t fight the infection, and have a high burden of the
organism, you’re probably not going to do so well…

Attached are relatively recent review papers on CNS and pulmonary
cryptococcal disease, as well as the most recent IDSA guidelines on management. Have a good weekend!